Chronic or persistent pain affects millions of adults each year with costs in lost work days, medical treatment and the reduction in the quality of life in the range of billions of dollars. Many of these conditions are gender-related. Women exhibit a higher prevalence of temporomandibular disorders, neuropathic pain, fibromyalgia, migraine headaches and some forms of arthritis. Furthermore, variations in hormonal levels associated with menstrual cycle, menopause, pregnancy and lactation influence pain levels. The purpose of this study is to evaluate the effects of progesterone and progesterone in combination with estrogen on the hyperalgesia and neuronal hyperexcitability associated with a rat model of persistent pain and inflammation. Our major hypothesis is that endogenous reproductive hormones can suppress persistent pain by their influence on a cascade of molecular, biochemical and physiological events at the spinal level involving inhibitory and excitatory amino acids and their receptors, and opioid peptides and their receptors. We will investigate the effects of these hormones on behavioral hyperalgesia, spinal cord neurons, modulation of GABA receptors, expression of opioid receptors and opioid peptides, and NMDA receptor function. Specific Aim 1 will characterize the changes in behavioral inflammatory hyperalgesia produced by progesterone, in lactating females, ovariectomized females with hormone replacement, and castrated males. Specific Aim 2 will determine the effects of progesterone on the development and maintenance of behavioral hyperalgesia, as well as the possible target sites of the antihyperalgesic effects in peripheral tissue, the spinal cord and the brain. Specific Aim 3 will determine that progesterone's antihyperalgesic effects are mediated, in part, via modulation of GABAA receptor activation. Specific Aim 4 will test the hypothesis that progesterone's antihyperalgesic effects are opioid-mediated, in part, at the level of the spinal cord. Specific Aim 5 will examine progesterone effects on NMDA receptor function and changes in NMDA receptor subunit gene expression following inflammation and hyperalgesia. In summary, we propose to elucidate the influence of reproductive hormones on mechanisms of persistent pain in a rat model that mimics human chronic pain conditions known to exhibit cyclical or pregnancy-related variations. The findings will be important for the development of new approaches to the management of these conditions.